Method of treating venous diseases

ABSTRACT

NOVEL THERAPEUTIC COMPOSITIONS CONTAINING RAUBASINE AND A METHOD OF USING THE SAME IN THE TREATMENT OF VENOUS DISEASES, INCLUDING THROMBOSIS, VARICOSIS, NON-CARDIAC EDEMA, ULCUS CRURIS VARIOSUM AND PERIPHERAL CIRCULATORY DISTURBANCES.

Feb. 16j', 1911 K, TMW ml. 3,564,094

METHOD 0F TREATIG VENOUS DISEASES (X.) l 12oo 20 30 40 50,60 5 1o 1520 25 5u INVENTOR.

Wauu/v6 SHA1/MANN United States Patent O U.S. CL 424-262 8 Claims ABSTRACT OF THE DISCLOSURE Novel therapeutic compositions containing raubasine and a method of using the same in the treatment of venous diseases, including thrombosis, varicosis, non-cardiac edema, ulcus cruris varicosum and peripheral circulatory disturbances.

The instant invention relates to therapeutic compositions containing the alkaloid raubasine, which is also known as ajmalicine, -yohimbine and tetrahydroserpentine and methods of using the same for the treatment of peripheral circulatory disturbances and particularly for the treatment of venous diseases.

The new methods of use and dosage of raubasine as disclosed herein depend upon a previously unknown and surprising mechanism of the action of this alkaloid. The present invention is also concerned with new pharmaceutical compositions in dosage unit form containing raubasine as active ingredient.

It is known that raubasine acts to reduce the resistance of the arterioles (Kroneberg, Arch. f. exper. Path. and Pharm., 233, 72/ 1958). Because of this effect, raubasine is used in the therapy of high arterial pressure in which the arterial resistance of all regions of the vessels is increased (Bachmann, Arzneimittelforsch., 10, 813/ 1960; Heintz and Losse, Dtsch, med. Wschr., 79, 1448/1954; and Thiele, Md. Wschr., l1, 645/1957). Furthermore, for this reason, raubasine has also been recommended for use in the therapy of peripheral circulatory disturbances (Lian, La Presse Medicale, 65, (66), 1477/1957; Dorst and Delange, La Vie Medicale, Medecine Therapeutique, N o. 46/ 1965; Perrin, `Gazette Medicale de France, No. 7/ 1965; and Pluvinage, ibid. No. 22/ 1965).

In connection with the above-mentioned therapeutic purposes, raubasine has been administered orally in the form of tablets at a dosage level of from l to at the most mg. Higher dosages have, apparently, been avoided because raubasine was considered to be a purely general arterial vasodilator. However, for the therapy of peripheral circulatory disturbances, a general arterial vasodilator is of no or only doubtful value. In the case of circulatory disturbances, the arterial resisance is only increased in a limited region of the vessels. Through a dilation of all of the vessels, the blood is, in particular, passed through the healthy regions of vessels which are able to dilate to a much greater extent than are the diseased ones. The blood pressure thereby drops so that the diseased regions of the vessels are, following the administration of an arterial vasodilator, more poorly supplied with fresh ice blood than previously (Hess, Die obliterierenden Gefsserkrangungen, pub. Urban and Schwartzenberg, 1959).

In accordance with the invention it has now, surprisingly, been found that the administration of raubasine effects an increase in the tone of the veins although it reduces that of the arteries and that, even in the case of comparatively large doses, the feared drop in the blood pressure, which impairs the blood supply to the diseased organs, does not take place.

This effect can be explained by the fact that the constriction of the capacitative vessels mobilizes the blood depot and the increased supply of blood to the heart increases the heart minute volume. However, the increased heart minute volume compensates the peripheral arterial vessel dilation and thereby prevents a drop in the blood pressure.

In experiments carried out on non-anaesthetized dogs and also on healthy human volunteers, it has now been found that the increase of the heart time volume and the decrease of the vessel resistance are balanced to such an extent that the mean arterial pressure does not decrease. As a result, a deterioration of the blood supply to organs having diseased vessels is avoided. It is ensured by this novel action of raubasine that the region supplied by the diseased vessels also profits from the increased blood circulation corresponding to the still available vessel reserve. Consequently, raubasine is superior to a pure vasodilator in the therapy of blood circulatory disturbances. The above-mentioned increase of tone of the veins is also indicative that raubasine is of value as a medicament in the treatment of conditions in which the venous system is itself diseased, as, for example, thrombosis prophylaxis, varicose prophylaxis, ulcus cruris varicosum and the therapy of edemas of non-cardiac origin.

Therefore, one of the new methods of use, according to the present invention, utilizing the alkaloid raubasine is in the treatment of peripheral blood circulatory disturbances utilizing orally the raubasine in dosage of at least 10 mg. per day and preferably of more than 30 mg. per day. Furthermore, in accordance with the invention it has been found that, in the case of peripheral blood circulatory disturbances, raubasin can also be administered intravenously, intra-arterially or intramuscularly. In the aforesaid blood circulatory disturbances, dosages of 10 to 40 mg. of raubasine per day have, in general, proved to be very useful. In particularly difficult cases, such as, for example, involving arterial embolism, the dosage of raubasine can be further increased to -200 mg. (intravenous infusion within a period of 18 hours) without untoward results.

Thus, according to the present invention, there are also provided therapeutic compositions, comprising raubasine in admixture with a sterile, liquid injectable pharmaceutical carrier therefor or in admixture with a solid, or liquid, orally administerable pharmaceutical carrier therefor and in the form of a dosage unit containing at least l() mg. raubasine.

The preferred liquid carrier is water which may contain the conventional additives employed for injectable solutions, such as stabilizers, solubilizers and buffers. Additives of this type include tartrate and citrate buffers, ethanol, complex-forming agents, such as ethylenediamine-tetraacetic acid and its nontoxic salts, and high molecular weight polymers, such as liquid polyethylene oxide, for viscosity adjustment.

The raubasine can also be administered orally in the form of a liquid, as, for example, in the form of a syrup containing the conventional additives such as stabilizers, flavoring agents, colorants, solubilizers, buffering agents, etc. In this connection, the syrups are preferably aqueous in nature but need not be so. It is also possible to provide the raubasine in the form of a highly concentrated solution or dispersion thereof in suitably prepared capsules.

The raubasine can also be administered in the form of tablets, capsules, powders, dragees and other like forms intended for oral administration. In this connection, the raubasine is provided in admixture with a solid pharmaceutical carrier.

As examples of solid pharmaceutical carriers, there may be mentioned starch, lactose, mannitol, methyl cellulose, talc, highly-dispersed silicic acid, high molecular weight fatty acid, such as stearic acid, gelatine, agar agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers, such as the polyethylene glycols. Such compositions intended for oral administration can, if desired, also contain a llavoring and/or sweetening agent.

Because raubasine is somewhat sensitive to light, i.e., it becomes brown colored after a time, compositions containing raubasine should be formulated and/or packaged so that this phenomenon is avoided. This difliculty can be overcome either by providing the compositions in brown glass tubes or, in the case of solid compositions, by making them in the form of dragees whereby each dosage unit has its own protection against light.

The following example is given as illustrative of an injection solution within the scope of the invention:

Raubasine mg 10.00 Tartaric acid mg 10.00 Citric acid mg 12.25 Spirit mg 32.00 Liquid polyethylene oxide (M W. about 400;

Lutrol 9) mg 200.00 Disodium salt of ethylene-diamine-tetraacetic acid (Titriplex III) mg 0.20 Sodium metabisulfite mg 0.50 Sodium hydroxide mg 1.63 Distilled water ml 3.00

In order to provide a combined systematic action with an especially intensive local vasodilation, up to 3 ampoules mg.) of raubasine can be injected intraarterially into the femoral artery. `In this case, there is obtained an especially marked increase of circulation in the muscle and skin of the diseased organ.

The following is given as illustrative of a therapeutic composition in accordance with the invention adapted for oral administration and constituting tablets of the following composition:

Mg. Raubasine 10.00 Starch 30.00 Lactose 30.00 Talc 6.00 Magnesium stearate 0.20 Agar agar 3.80

For a prolonged treatment, 3-4 tablets in the form of dragees are given.

In carrying out clinical investigations with raubasine, the following elects were, in particular, observed:

(l) Patients presenting obstructed conditions due -to venous diseases evidenced, following raubasine therapy, an almost complete regression of the edema which, when application of the raubasine therapy is interrupted, again 4 increases and again regresses upon the renewed administration of raubasine.

(2) Patients presenting obstructed conditions due to diseases of the venous system evidenced, following administration of raubasine, an almost complete regression of the obstruction so that wearing of elastic stockings was no longer necessary.

(3) A patient sulfering from ulcus cruris varicosum had his condition favorably inuenced by raubasine. The ulcers with which he was affected were healed as a result of treatment with raubasine.

(4) In a number of patients having various types of fractures, the edema associated with such fractures was dispersed more quickly when the patient was simultaneously treated with raubasine than in those instances where no raubasine therapy was employed.

(5) Patients affected with malignant tumors who, in a post-operative state, exhibit a pronounced edematous condition, evidenced a remarkable dispersion of this edema and a regression of localized swelling following treatment with raubasine.

These results were obtained by treating with good success more than 5,000 persons.

From the above clinical results, the following new uses for raubasine are indicated:

(l) Thrombosis prophylaxis:

Raubasine leads to an acceleration of the circulation. (2) Varicose prophylaxis:

The increase of venous tone counters the formation of varicoses. Increased ow in the dilated veins is obtained. Therefore, the passive dilation stimulus, which inevitably leads to the formation or strengthening of varicoses, is absent.

(3) Ulcus cruris varicosum:

As a result of the acceleration of the llow and increased tone in the venous circulation region, the edema associated with this condition is dispersed. Thereby, there results an improved circulation in the tissue, which avoids the formation of ulcera crura or promotes healing of any already existent ulcers.

(4) Therapy of edemas of non-cardiac origin:

In the cases of conditions following fractures, after venous thromboses, tumors and other venous-occasioned impairments of flow, there results the opening of venoles due to the increased venous tone in comparison with the tissue pressure. As a result, there is produced, together with the overall effect of the raubasine, an increased circulation with acceleration of the flow and dispersion of the edema.

The action of raubasine on the venons tone and on the whole circulation was determined and evaluated by the following experiments carried out on dogs and healthy human volunteers:

(l) Experiments with narcotized dogs In 5 cross-bred dogs having a weight of 9-14 kg., there were measured synchronously and recorded, maintained in a state of morphine-butallylonal narcosis, the arterial pressure in the aorta, the central venous pressure (at the height of the right ventricle) and the peripheral venous pressure in one of the femoral veins by means of electrical pressure transformers; the arterial ilow-time volumes in the aorta abdominalis above the iliac fork and the venous How-time volumes in a vena cava caudalis shortly above the junction of the iliacal veins was determined by means of electromagnetic ow probes. A high chronological resolving power permitted the determination of the interesting circulation parameters at intervals of l0 seconds. In the aforesaid experiments, raubasine, in the forms of its phosphate, was dissolved in 5.5% aqueous glucose solution, with the addition of 5% dimethyl formamide. 2 mg./kg. raubasine, as base, were injected intravenously,

The results which were obtained are summarized in the following Table 1 which follows:

6 vestigation of the volume elasticity coefficients before and 2 and 30 minutes after the intravenous injection of 2 TABLE 1 Seconds after i.v. injection of 2.0 ing/kg. raubasine Control Circulatory Parameters values 10 20 30 40 50 60 120 (1) tmm. Hg] 96 102 101 99 94 97 95 92 (2) Frm [111111. '1] 141 No 10 sec. measurements 126 156 (3) X'a [ml. 10 sec. 1] 46. 5 56. 5 68.0 73.0 70. 0 66. 2 62. 3 65 (4) [ml. 10 sec. 1] 46.0 70.0 79. 5 73. 2 68. 5 64. 0 61.0 63. 5 (5) i.. [111111.11120 +6 +12 +42 +30 +19 +14 +13 +6 (6) pw lmm. H20] +7 +50 +46 +35 +20 +13 +14 +12 7) vvv. [m1 10 se@ -1] 0. 5 +13. 5 +11. 5 +0. 2 -1. 5 2. 2 -1. s 1. 5 (8) w-pn [111111. H20] +1 +38 +4 +5 +1 -1 +1 (6) pp=mean peripheral venous pressure in the vena femoralis (7) \.7V=diierence between venous outflow and arterial inflow (8) pvpu=ditference between peripheral and central venous pressure.

As can be seen from Table 1, only 10 seconds following the injection of raubasine, the arterial inow and mgm/kg. raubasine. These experiments were carried out, the results obtained are set out in Table 2 which follows:

TABLE 2 Minutes after iv. injection of 2.0 mg./kg.

raubasine Control 2 30 Before 5sec.after Before 5sec. after Before 5sec.ater

occlusion occlusion occlusion occlusion occlusion occlusion (1) 5l, [mm H2O] +5 +28 +7 +358 +3 +41 (2) Apw Imm. H2O] +23 +51 +38 (3) AVol [1111. 5 sec. J] 24 37 33 (4) Even [m1n. H2O 5 see/1111.] 0. 96 1. 38 1. 15

NOTE .-(1) Bw=mean periphesal venous pressure before and 5 seconds after venous occlusion (2) Af) ,=ncrease of peripheral venous pressure within 5 seconds (3) AVol=inerease of volume in 5 seconds (4) Even=elasticity coefficient of the peripheral veins defined as Ap/Avol.

the venous outow had increased. However, this increase in circulation demonstrates, arterially and venously, a clearly different course, as the difference between venous outflow and arterial inflow clearly shows (line 7 of Table 1). For up to 20 seconds following injection, the venous outflow was greater than the arterial inflow. When the values for the pressure difference between the peripheral and central venous pressures are compared, then it can be seen that, synchronously with the relatively higher venous outflow, the peripheral venous pressure has also increased more markedly than the central venous pressure (line 8 of Table 1). Such a rapidly commencing increase of the peripheral venous pressure is to be attributed to a constriction of the capacitative vessels, i.e., to an increase of venous tone. This mechanism brings about a primary mobilization and displacement of blood from the capacitative vessels in the direction of lower venous pressure, i.e., in the direction of the heart, which then increases its output volume corresponding to the increased supply. Only in the second place does there take place an adaptive dilation of the arterial resistance vessels caused by the direct action of the raubasine. However, in the case of the primarily increased blood time volume, a decrease of the arterial pressure does not result.

The venous tone or the expansion resistance of the vessel wall is proportional to the pressure increase and inversely proportional to the volume increase per unit time and can be mathematically dened as the volume elasticity coeflicient 13en given by the equation:

AIP- VCR A vol The above-described experimental procedure allowed for, by temporary occlusion of the flow-olf veins, an in- From Table 2, line 4, it can be seen that the expansion resistance, i.e., the venous tone, increased by the action of the alkaloid raubasine and that this increase could still be detected 3() minutes following injection thereof.

(2) Experiments with non-anaesthetized dogs and healthy human volunteers In studies using non-anaesthetized dogs, the heart minute volume was continuously measured in the aorta ascendens by means of chronically implanted electro-magnetic flow probes. The procedure followed in carrying out the flow measurement was that of Kolin and Kado (Proc. Nat. Acad. Sci., 45, 1313/1959) as well as of Khouri and Gregg (I. appl. Physiol., 18, 224/ 1963) and involved the use of flow probes as manufactured by the firm of Biotronex Inc. As the calibration of the llow probe on nonanaesthetized animals is very difficult to carry out, the heart minute volume and the values dependent thereon, such as the beat volume and the peripheral resistance, are expressed as a percentage of the initial values.

For the measurement of arterial blood pressure, catheters were chonically implanted in the aorta. The mean arterial pressure values were indicated by a Statham strain gauge type P 23 Db.

In order to obtain values for the registration of the central venous pressure, catheters were inserted from the vena jugularis up to the height of the heart and first allowed to heal in situ.

In obtaining values for the human volunteers, the blood pressure was measured on the upper arm by the method of Riva-Rocci and the heart minute volume by the method of Wezler and Boger (Naunyl-Schmiedebergs Arch. exp. Path und Pharmak., 184, 482/1937).

In Table 3, which follows, there are summarized the results of the experiments on non-anaesthetized dogs following the intravenous injection of 5.0 mg./ kg. raubasine and in FIGS. l and 2 of the accompanying drawings there are compared the circulatory analyses on dogs and humans, respectively. In the case of dogs, during the first minutes following the injection of raubasine several analyses were carried out at short intervals of time. In this iirst phase of the action of the raubasine, there was obtained a considerable increase in the heart minute volume with the preponderant participation of the heart beat volume, whereas the heart rate increased only slightly. Synchronously with this first increase of the heart minute volume, there was observed a remarkable increase of the pressure in the right ventricle.

In the case of humans, 20 mg. raubasine were administered intravenously and circulatory analyses carried out over comparatively large intervals of time. The results Were, in principle, the same as in the case of dogs. The blood pressure did not drop. Corresponding to the increased beat volume, there was only observed an increase of the blood pressure amplitude, 3 minutes following the injection. The central venous pressure was admittedly not measured, but, having regard to the constant mean arterial pressure, it can be safely assumed, ywithin the limits of probability, that, in the case of man, too, the increase of the heart minute volume is the result of an increased blood supply.

Note-(1) 5. =niean arterial pressure (2) Frm =heart rate (3) Vm =heart minute volume (4) Vm :heart beat volume (5) W =peripl1eral vessel resistance (6) Pult. dem. =pressure in right ventricle.

In FIG. 1, there are graphically shown the mean results obtained from 16 experiments on non-anaesthetized dogs following the intravenous injection of 5 mg./ kg. raubasine and in FIG. 2 there are graphically shown the mean results obtained from experiments on human volunteers following the intravenous injection of 20 mg. raubasine. In these two gures, the following abbreviations have been used:

P=blood pressure in mm. Hg

Frcor=heart rate VSM-:cardiac output W=periphera1 vascular resistance Pm, denn-:central venous pressure Vcor=heart beat volume Ps/Pd=systolic/diast0lic pressure in mm. Hg

If there is taken into account the stability of the mean arterial pressure, the absence of a clear increase in heart rate and the brief increase of the venous pressure, then the increase of the heart minute volume is primarily a result of the depot blood mobilized on the venous side of the circulation and made available to the heart. Consequently, the reduction of the peripheral resistance takes place preponderantly pressure passively.

After passing through a short counter-regulatory phase, a relatively stable circulatory position is reached, the characteristics of which are the increased heart minute volume with reduced peripheral vessel resistance and unchanged arterial pressure values.

The increase of the blood time volume as a result of an increased venous supply clearly distinguishes raubasine from the large number of so-called vasodilators, insofar as a justifiably feared blood pressure reduction does not occur and thus optimum conditions are provided for the promotion of a pathologically reduced blood circulation.

What is claimed is:

1. A method of treating a human subject afflicted with a venous disease selected from the group consisting of venous thromboses, venous varicoses, non-cardiac edemas, cruris varicosum and peripheral venous circulatory disturbances which comprises administering to said subject raubasine in an amount of from 10 to 200 mg.

2. A method according to claim 1 which comprises administering said raubasine in an amount of from l0 to 30 mg. per day.

3. A method according to claim 1 which comprises administering said raubasine in an amount of from 30 to 200 mg. per day.

4. A method according to claim 1 in which the venous disease is venous thrombosis.

5. Method according to claim 1 in which the venous disease is venous varicosis.

6. Method according to claim 1 in which the venous disease is non-cardiac edema.

7. Method according to claim 1 in which the disease is nlcus cruris varicosum.

8. A method according to claim 1 in which the venous disease is arterial embolism and said raubasine is administered daily in an amount of from 10() to 200 mg. by intravenous infusion Within a period of 18 hours.

Kroneberg, Pharmakologie des Rauwolfia-Alkaloids Raubasin (S-Yohimbin-Ajmalicin), Arch. Exper. Path. U. Pharmakol., vol. 233, pp. 72-78, 94-96, (1958).

STANLEY J. FRIEDMAN, 'Primary Examiner D. J. FUNDERBURK, Assistant Examiner (go UNITE!) S'IJA'I'IS PATINT OFFICE CER'IFI.CATH Ol" CORR EC'IION Patent No. 3, 564,094 Dated February 16 1971 Inventor(s) l) Karl Dietmann 2) Gunter Steinorth l 3) Wolfgang Schaumann It is certified that error appears in the above-identified patel and tht said Letters Patent are hereby corrected as shown below:

Column l, line 4l "Md." should read Med.-

Column 2, lines l and 2 "Gefsserkrangungen" should read --Gefsserkrankungen Column 5, Table l Last item in last column should read +6 Column 6 1st line of Table 2, 4th column "+358" should read +58 Column 6, line 72 "Naunyl" should read Naunyn Column 8, line 34 After the word "edemas," insert u1cus Signed and sealed this 20th day of July 1971.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR. Attesting Officer Commissioner of Patents 

